Alzheimer's disease (AD) is notably the most prevalent form of dementia afflicting the elderly and is associated with a multitude of genetic, environmental, epigenetic, dietary and lifestyle risk factors1. AD is said to affect in excess of 37 million people globally4.
The neuropathological hallmarks of AD include intracellular neurofibrillary tangle formation and extracellular amyloid beta peptide (Aβ) plaque deposition5. The sequential cleavage of the amyloid precursor protein (APP) by beta (β) and gamma (γ) secretases2 results in the shedding of the 4 kDa Aβ which aggregates to form amyloid plaques. Aβ, as a soluble oligomer, as well as plaque-incorporated aggregate, is the predominant focus of investigative efforts to treat AD.
Aβ and more specifically the 42 amino acid isoform (Aβ42), is largely considered the primary disease causing agent in AD (as Aβ accumulation is a pre-requisite for tau hyperphosphorylation, another AD-associated protein)6. Specifically, Aβ is generated through the proteolytic cleavage of the type I transmembrane protein APP by β- and γ-secretase. The mechanisms underlying Aβ induction of neuronal loss (one of the key pathophysiological features of AD) are yet to be firmly established. It is proposed that the neurotoxicity of Aβ is partially mediated through its interactions with cellular receptors. These interactions may include binding of Aβ to a surface receptor on a neuron thereby changing its biochemical structure, which negatively affects neuronal communication. It is proposed that Aβ may affect neuronal communication by eliciting alterations in signal transduction pathways through direct binding to cell surface receptors, (such as N-methyl-d-aspartate (NMDA) receptors, insulin receptors, α-7 nicotinic receptors)3,7. Alternatively, Aβ may alter signal transduction pathways indirectly via incorporation into lipid membranes of the plasma membrane and, to a lesser extent, cellular organelles8. This is thought to induce structural and functional alterations in lipid bound receptors and consequently results in aberrant signal transduction pathways8.
There is a need for compounds which in use modulate the production and concentrations of APP, (β) and (γ) secretases and Aβ in a human or animal in order to treat AD. There is a further need for compounds that modulate intracellular neurofibrillary tangle formation and extracellular Aβ plaque deposition in order to treat AD.